Estrogen receptor (ER) regulates transcription in conjunction with the action of coregulatory molecules that interact with the receptor in a ligand-dependent fashion. The gene for one of these ER coregulators, AIB1, is amplified in a subset of human breast cancers and functions as an oncogene. Work from several labs including our own have implicated AIB1 and other coregulators in determining the tissue and tumor-specific activities of selective estrogen receptor modulators (SEiRMs) such as tamoxifen and as playing a role in tamoxifen resistance. Aromatase inhibitors (Al) have replaced tamoxifen as first-line endocrine therapy for post-menopausal women with advanced ER+ breast cancer and are rapidly replacing tamoxifen in early stage ER+ breast cancer as well. However, little is known concerning the mechanism underlying de novo resistance to Al therapy. We hypothesize that the levels and activity of A1B1 and other ER coregulators play a role in determining a tumor's response to Al therapy. We will test this hypothesis in cell-based models of estrogen deprivation, a transgenic mouse model of A1B1-dependent breast cancer, and in the pre-surgical setting in postmenopausal women with newly diagnosed ER+ breast cancer. These studies will facilitate the translation of progress in our basic understanding of the importance of coregulators in ER action to improvements in endocrine therapy.